Genetic Susceptibility to Distinct Bladder Cancer Subphenotypes

Lin T. Guey, Montserrat García-Closas, Cristiane Murta-Nascimento, Josep Lloreta, Laia Palencia, Manolis Kogevinas, Nathaniel Rothman, Gemma Vellalta, M. Luz Calle, Gaëlle Marenne, Adonina Tardón, Alfredo Carrato, Reina García-Closas, Consol Serra, Debra T. Silverman, Stephen Chanock, Francisco X. Real, Núria Malats

Research output: Contribution to journalArticle

Abstract

Background: Clinical, pathologic, and molecular evidence indicate that bladder cancer is heterogeneous with pathologic/molecular features that define distinct subphenotypes with different prognoses. It is conceivable that specific patterns of genetic susceptibility are associated with particular subphenotypes. Objective: To examine evidence for the contribution of germline genetic variation to bladder cancer heterogeneity. Design, setting, and participants: The Spanish Bladder Cancer/EPICURO Study is a case-control study based in 18 hospitals located in five areas in Spain. Cases were patients with a newly diagnosed, histologically confirmed, urothelial cell carcinoma of the bladder from 1998 to 2001. Case diagnoses were reviewed and uniformly classified by pathologists following the World Health Organisation/International Society of Urological Pathology 1999 criteria. Controls were hospital-matched patients (n = 1149). Measurements: A total of 1526 candidate variants in 423 candidate genes were analysed. Three distinct subphenotypes were defined according to stage and grade: low-grade nonmuscle invasive (n = 586), high-grade nonmuscle invasive (n = 219), and muscle invasive (n = 246). The association between each variant and subphenotype was assessed by polytomous risk models adjusting for potential confounders. Heterogeneity in genetic susceptibility among subphenotypes was also tested. Results and limitations: Two established bladder cancer susceptibility genotypes, NAT2 slow-acetylation and GSTM1-null, exhibited similar associations among the subphenotypes, as did VEGF-rs25648, which was previously identified in our study. Other variants conferred risks for specific tumour subphenotypes such as PMS2-rs6463524 and CD4-rs3213427 (respective heterogeneity p values of 0.006 and 0.004), which were associated with muscle-invasive tumours (per-allele odds ratios [95% confidence interval] of 0.56 [0.41-0.77] and 0.71 [0.57-0.88], respectively) but not with non-muscle-invasive tumours. Heterogeneity p values were not robust in multiple testing according to their false-discovery rate. Conclusions: These exploratory analyses suggest that genetic susceptibility loci might be related to the molecular/pathologic diversity of bladder cancer. Validation through large-scale replication studies and the study of additional genes and single nucleotide polymorphisms are required.

Original languageEnglish (US)
Pages (from-to)283-292
Number of pages10
JournalEuropean Urology
Volume57
Issue number2
DOIs
StatePublished - Feb 1 2010

Keywords

  • Genetic polymorphism
  • Heterogeneity
  • Pathologic characteristics
  • Tumour subphenotypes
  • Urinary bladder cancer

ASJC Scopus subject areas

  • Urology

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    Guey, L. T., García-Closas, M., Murta-Nascimento, C., Lloreta, J., Palencia, L., Kogevinas, M., Rothman, N., Vellalta, G., Calle, M. L., Marenne, G., Tardón, A., Carrato, A., García-Closas, R., Serra, C., Silverman, D. T., Chanock, S., Real, F. X., & Malats, N. (2010). Genetic Susceptibility to Distinct Bladder Cancer Subphenotypes. European Urology, 57(2), 283-292. https://doi.org/10.1016/j.eururo.2009.08.001